The prevention or inhibition of inflammation and adhesion formation is of significant concern to medical professionals.
Adhesion formation is a final common physiological result of inflammation from any cause. Although it is commonly seen following surgery, it can also occur in many other clinical settings. In the post-operative setting, serious scar and/or adhesion formation can occur, greatly increasing patient morbidity. If this serious complication could be avoided, great savings could be realized in health care costs by reducing the need for future hospitalizations and therapeutic interventions. Furthermore, if adhesion formation is prevented, many chronic diseases could be prevented or at least mitigated.
In response to any tissue injury, the body will attempt to heal itself. The manner in which the body responds to an initial injury can frequently determine whether a person will return to normal health or develop significant chronic disease. For example, adhesions are an undesirable biological response to tissue injury. They sometimes occur post-operatively, but may also occur after other forms of injury such as infection and trauma.
The healing process is mediated by the immune response. The immune system is a protective network that enables the body to ward off disease. For example, a microorganism, such as a bacteria or virus, can invade the body and thereby activate the immune system. Under normal circumstances, the host is protected when the invading microorganism is eliminated.
The body's host mechanism, in attempting to heal areas of injury, sometimes mounts an overly aggressive immune response. This undesirable reaction can lead to scar formation and/or adhesions. This "hyper" immune response is also the cause of a group of illnesses known as "autoimmune" diseases which include rheumatoid arthritis, systemic lupus erythematosis, thyroiditis, inflammatory bowel disease, allergies, and many chronic dermatologic diseases such as psoriasis and eczema. Recently researchers have presented evidence that atherosclerosis or "hardening of the arteries" is also mediated via this "hyper" immune response.
Often the immune response is associated with increased blood flow and increased vascular permeability. This causes the release of white blood cells, macrophages, platelets and other cellular elements to the surrounding tissues. These cells are the harbingers of inflammation. By blocking or restricting the immune response and by inhibiting certain cellular functions, the formation of excessive scar tissue can be inhibited. While adhesion formation results to some extent for all large inflammations or in instances where marked cell damage has occurred, adhesion formation generally results from an overly aggressive immune response mounted by the host in an attempt to heal the injured tissue.
Prostaglandins are a family of compounds which have been identified as playing a significant role in inflammation. Their biosynthesis is triggered by the release of arachidonic acid, a preliminary event in the immune response. Prostaglandins are produced throughout the body and are derived from enzymatic action on a common substrate, arachidonic acid. The first step in prostaglandin synthesis is the oxygenation of arachidonic acid by the enzyme cyclooxygenase. The oxygenated prostaglandin precursors are subject to further enzymatic processes which provide the various members of the prostaglandin family.
Closely related in structure and function to the prostaglandins are a family of compounds known as leukotrienes. Leukotrienes are also derived from arachidonic acid metabolism, but through the lipoxygenase pathway. Like prostaglandins, leukotrienes exhibit inflammatory properties.
Arachidonic acid is an essential fatty acid consisting of twenty carbon atoms and containing four carbon-carbon double bonds. By virtue of the position of the carbon-carbon double bond at the methyl (omega) end of the hydrocarbon chain, it is classified as an omega-6 fatty acid. A closely related family of fatty acids are the omega-3 fatty acids. In addition to double bond position, omega-6 and omega-3 fatty acids may also be distinguished by their origins. The precursors to these fatty acids are derived from botanical and/or marine plants which are in turn further metabolized in animals to provide the long chain polyunsaturated acids. Omega-6 fatty acids may be found predominantly in land animals, while omega-3 fatty acids are abundant in fish.
In principle, any immune response may be modulated by stimulation or suppression--that is, immunomodulation may be accomplished through the use of immunostimulants or immunosuppressants (collectively referred to as immunomodulators). Therefore, immunomodulators may be effective in treating inflammatory conditions and preventing adhesion formation.
To this end, it is believed that inhibition of the enzymatic pathways which yield prostaglandins and leukotrienes would result in decreased production of these compounds and a consequent reduction in their inflammatory effects. The inhibitors of these enzymatic pathways are thus immunomodulators of the immune response.
As mentioned above, adhesion formation has been attributed to overly aggressive immune response. One class of compounds which has been identified as immunostimulants are interleukins. Interleukins are soluble immuno-enhancing glycoproteins produced by T-lymphocytes and have been commonly utilized as treatments to restore and/or bolster immune response in immunodeficient conditions. Accordingly, compounds which inhibit interleukin production are also immunomodulators. Such inhibitors are believed to suppress interleukin production and, consequently, immune response thereby effectively inhibiting both inflammation and adhesion formation.
Despite the great need to inhibit adhesion formation, current therapeutic options and preventive measures are of little or limited effectiveness. Accordingly, there is a need in the art for compositions which effectively modulate immune response and prevent, inhibit, or provide treatment for inflammation and adhesion formation. The present invention fulfills these needs, and provides further related advantages.